Breast cancer is a heterogeneous disease that is categorized into molecular and histopathological subtypes based predominantly on analysis of hormone and growth factor receptors—namely estrogen (ER), progesterone (PR), and HER2/Erbb2 (Her2). Women with triple-negative breast cancer (TNBC; i.e. ER−/PR−/Her2−) are at the greatest risk of early recurrence. Luminal breast cancers (LBC), which often include ER+ tumors, are the most prevalent form of breast cancer. These tumors are often differentiated and associated with good prognosis, yet some patients with LBC experience recurrent disease even 15-20 years after their initial diagnosis and surgery. Although classification into these categories has some correlation with patient outcome, it is difficult to accurately predict which patients will relapse. Furthermore, there is no correlation between molecular classification and patient response to current treatment therapies.
In some patients with metastatic breast cancer, tumor cells clearly disseminate prior to surgery, but remain undetected for protracted periods of time before the patient becomes symptomatic. Incipient primary tumors and second primary tumors can also exist in a state of indolence before being detected. For example, autopsy studies of people without a medical history of cancer revealed that indolent cancers are highly prevalent within the general population. What causes indolent tumors to erupt into overt disease is unknown, making it difficult to predict which cancer patients are likely to relapse or to benefit from preemptive therapy.
The systemic environment is appreciated as an important determinant of tumor malignancy and progression. It was previously established that indolent cancer cells (“responders”) that are disseminated to various anatomical locations within host mice can be stimulated to form malignant tumors as a consequence of aggressively growing triple-negative breast tumors, luminal breast cancer tumors and colon tumor samples located at distant anatomical sites. These tumors are seen as “instigators” or inducers of the transformation and conversion of the indolent cancer responder cells to form malignant tumors. A growing body of evidence supports the notion that tumors that co-exist within a patient who has multiple tumor burden (e.g., multiple disseminated metastases) can interact systemically to modulate overall cancer progression. Responding tumor outgrowth occurs as a consequence of systemically-acting cytokines and bone marrow derived cells that are rendered pro-tumorigenic by the instigating triple-negative breast tumors. This cascade of events, termed “systemic instigation”, results in the outgrowth of highly desmoplastic, malignant tumors. A deeper understanding of systemic tumor-promoting processes should improve identification of patients who would benefit from adjuvant therapy.